Desymmetrization of cyclohexadienones via intramolecular stetter reaction to construct tricyclic carbocycles

Article abstract of DOI:10.1055/s-0033-1338838

N-Heterocyclic carbene catalyzed desymmetrization of cyclohexadienones to construct tricyclic carbocycles via an intramolecular enantioselective Stetter reaction was realized. With 10 mol% of d-camphor-derived triazolium salt E and 10 mol% of KOAc, various substituted tricyclic carbocycles bearing a quaternary carbon stereogenic center and two contiguous stereocenters were obtained in excellent yields with up to 89% ee. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338838

CLUSTER
▌1201
cluster
Desymmetrization of Cyclohexadienones via Intramolecular Stetter Reaction
to Construct Tricyclic Carbocycles
Desymmetrization of Cyclohexadienones
Min-Qiang Jia, Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, P. R. of China
Fax +86(21)54925087; E-mail: slyou@sioc.ac.cn
Received: 08.04.2013; Accepted after revision: 29.04.2013
O
Abstract: N-Heterocyclic carbene catalyzed desymmetrization of
H
HO
B(OH)2
Suzuki
coupling
cyclohexadienones to construct tricyclic carbocycles via an intra-
molecular enantioselective Stetter reaction was realized. With
10 mol% of D-camphor-derived triazolium salt E and 10 mol% of
KOAc, various substituted tricyclic carbocycles bearing a quaterna-
ry carbon stereogenic center and two contiguous stereocenters were
obtained in excellent yields with up to 89% ee.
HO
+
R2
O
H
R2
Br
Key words: camphor, desymmetrization, N-heterocyclic carbene,
organocatalysis, Stetter reaction
R1O
Stetter
reaction
R1O
O
R2
∗
dearomatization
O
R2
∗
N-Heterocyclic carbene (NHC) catalyzed umpolung
reactions1 provide an unconventional way for the synthe-
sis of target molecules.2 Among these, the Stetter reaction
is undoubtedly one of the most important reactions in con-
structing novel structures.2,3 On the other hand, dearoma-
tization of phenols together with desymmetrization
reaction is an important strategy in building molecular
complexity from readily available starting materials.4,5 In
2006, Rovis et al. combined dearomatization of phenols
with desymmetrization reaction via N-heterocyclic car-
bene catalyzed Stetter reaction to construct hydrobenzo-
furans.6 Inspired by their pioneering works, we recently
applied dearomatization of phenols–asymmetric Stetter
reaction to construct chiral tricyclic N-heterocycles.7
However, there were few studies on the construction of
carbocycles via the dearomatization–desymmetrization
strategy likely due to the difficulty to access the corre-
sponding substrates.8 As our continuing interests in
dearomatization5,7 and NHC catalysis,7,9 we envisaged
that tricyclic carbocycles could be synthesized efficiently
via NHC-catalyzed Stetter reaction given the suitable de-
sign of substrates. As seen from Scheme 1, Suzuki cou-
pling reaction could be used to synthesize para-
substituted phenols. Then the combination of dearomati-
zation of phenols and desymmetrization via an intramo-
lecular Stetter reaction would furnish the tricyclic
carbocycles. Notably, the constructed tricyclic carbocy-
cles exist in a number of natural products.10 In this paper,
we report our preliminary results on this subject.
CHO
O
OMe
OH
HO
H
OH
O
O
HO
H
COOH
H
O
gibberellic acid
(–)-taiwaniaquinol B
OH
H
HO
HN
H
H
veratramine
Scheme 1 Reaction design and natural products containing tricyclic
carbocycles
derived triazolium salt11 E as the NHC precursor. The re-
sults are summarized in Table 1.
When a strong base such as KHMDS was used, the reac-
tion ran smoothly to give product 2a in 96% yield albeit
with only 5% ee (Table 1, entry 1). All the tested organic
bases including DBU, Et3N, and DIEA gave the desired
products in moderate yields and enantioselectivities, and
the enantioselectivity of product 2a increased slightly
with weak bases (Table 1, entries 2–4). The desired prod-
uct 2a was obtained in up to 96% yield and 70% enantio-
meric excess when a weak inorganic base such as NaOAc
was utilized (Table 1, entry 5). To our delight, the reaction
with KOAc or CsOAc gave the best enantioselectivity
(92–96% yields, 79% ee, Table 1, entries 7 and 8). Other
inorganic bases such as LiOAc, NaHCO3, K3PO4, KOt-Bu,
and Cs2CO3 were all suitable bases to afford the desired
products with moderate enantioselectivities (31–67% ee,
Table 1, entries 6, 9–12).
We began our study by choosing 1a as a model substrate.
Firstly, various bases were screened with D-camphor-
SYNLETT 2013, 24, 1201–1204
Advanced online publication: 17.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338838; Art ID: ST-2013-R0310-C
© Georg Thieme Verlag Stuttgart · New York

1202
M.-Q. Jia, S.-L. You
CLUSTER
Table 1 Screening of Basesa
Various substituted substrates were subjected to the opti-
mized reaction conditions to examine the generality of the
reaction. The results are summarized in Table 4. The in-
fluence of the R1 substituent was firstly investigated. Sub-
strates with a methyl or ethyl substituent proceeded
smoothly to afford their desired products in excellent
yields and enantioselectivities (87–90% yields, 88–89%
ee, Table 4, entries 1 and 2). The substrate with an acetyl
substituent gave a complex reaction mixture (Table 4, en-
try 3). Substrates having electron-withdrawing substitu-
ents (4-F, 5-F, 6-F, 5-Cl) on the phenyl group were tested,
and the desired products were obtained in excellent yields
and enantioselectivities (87–96% yields, 86–89% ee, Ta-
ble 4, entries 4–7). The substrates with electron-donating
groups such as 5-MeO, 4-Me, or 5-Me also ran smoothly
providing the desired products in excellent yields and
good enantioselectivities (95% yield, 81–85% ee, Table 4,
entries 8–10). To our delight, the substrate with an allyl
group can also be tolerated affording the functionalized
product 2k with 91% yield and 85% enantiomeric excess
(Table 4, entry 11).
BF4
C6F5
N
N
N
O
MeO
O
MeO
O
E (10 mol%)
*
H
*
base (10 mol%)
toluene
O
O
1a
2a
Entry
Base
Time (h)
Yield (%)b ee (%)c
1
2
KHMDS
DBU
12
48
48
48
24
48
6
96
45
45
72
96
77
96
92
94
95
93
64
5
36
50
60
70
67
79
79
50
31
51
34
3
Et3N
4
DIEA
5
NaOAc
LiOAc
KOAc
CsOAc
NaHCO3
K3PO4
KOt-Bu
Cs2CO3
6
In summary, N-heterocyclic carbene catalyzed enantiose-
lective desymmetrization of cyclohexadienones to con-
struct tricyclic carbocycles via an intramolecular Stetter
reaction was developed. With 10 mol% of D-camphor-
7
8
2
9
48
12
12
48
Table 2 Screening of Solventsa
10
11
12
BF4
C6F5
N
N
N
O
a Reaction conditions: 1a (0.2 mmol), E (10 mol%), base (10 mol%),
toluene (2.0 mL), r.t.
MeO
O
MeO
O
E (10 mol%)
*
b Isolated yield of 2a.
H
*
c Determined by HPLC.
KOAc (10 mol%)
solvent
O
O
1a
2a
In the presence of 10 mol% of triazolium salt E and
KOAc, various solvents were further screened. The re-
sults are summarized in Table 2. The reaction in all
screened solvents except MeOH ran smoothly to afford
the desired product 2a in moderate to excellent yields. The
reaction in MeOH only led to a trace amount of the desired
product 2a (Table 2, entry 7). Reactions in ether-type sol-
vents in general led to higher enantioselectivity, and the
highest enantioselectivity (86% ee) was obtained in di-
ethyl ether (Table 2, entries 8–11).
Entry
Solvent
Time (h)
Yield (%)b ee (%)c
1
2
toluene
o-xylene
CH2Cl2
CHCl3
CCl4
6
1
96
98
96
92
94
90
trace
76
60
95
94
79
81
73
71
74
74
–
3
16
6
4
5
3
With KOAc as the base, diethyl ether as the solvent, sev-
eral readily available chiral NHC precursors were then ex-
amined. In the presence of D-camphor-derived NHC
precursors A–C11a or the aminoindanol-derived NHC pre-
cursors F–H,12 low to moderate enantioselectivities were
obtained, while D-camphor-derived NHC precursor D11a
led to the formation of only trace amount of product. Fur-
ther examination of other reaction parameters such as re-
action temperature, substrate concentration, and loading
6
cyclohexane
MeOH
THF
1
7
16
16
16
24
6
8
83
77
83
86
9
dioxane
DME
10
11
Et2O
of the base led to the following optimized reaction condi- a Reaction conditions: 1a (0.2 mmol), E (10 mol%), KOAc (10
mol%), solvent (2.0 mL), r.t.
tions: 10 mol% of E, 10 mol% of KOAc, diethyl ether,
0 °C (90% yield, 89% ee, Table 3, entry 9).
b Isolated yield of 2a.
c Determined by HPLC.
Synlett 2013, 24, 1201–1204
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Desymmetrization of Cyclohexadienones
1203
Table 3 Screening of Catalystsa
Table 4 NHC-Catalyzed Enantioselective Desymmetrization of Cy-
clohexadienonesa
O
MeO
MeO
O
*
BF4
cat. (10 mol%)
C6F5
H
*
KOAc (10 mol%)
Et2O, r.t.
N
N
N
O
O
O
3R1O
R1O
1a
O
2a
O
4
∗
E (10 mol%)
2
BF4
O
BF4
R2
R2
∗
H
Ar
5
KOAc (10 mol%)
Et2O, 0 °C
1
N
N
N
6
N
N
O
O
1
2
N
Ar
O
Entry
R1
R2
Product Time
(h)
Yield
(%)b
ee
A Ar = Ph
B Ar = 4-MeOC6H4
C Ar = 2,4,6-Me3C6H2
D Ar = 3,5-(F3C)2C6H3
E Ar = C6F5
(%)c
F Ar = C6F5
G Ar = 2,4,6-Me3C6H2
H Ar = 3,5-(F3C)2C6H3
1
2
Me
Et
H
2a
2b
–
24
16
24
21
16
12
3
90
89
88
–
H
87
Entry
Cat.
Time (h)
Yield (%)b ee (%)c
3
Ac
Me
Me
Me
Me
Me
Me
Me
H
messy
91
1
2
A
B
C
D
E
F
30
30
30
30
6
15
11
73
trace
96
96
74
51
90
96
96
31
31
8
4
4-F
5-F
6-F
5-Cl
5-MeO
4-Me
5-Me
H
2d
2e
2f
86
88
89
86
81
85
84
85
5
87
3
6
92
4
–
7
2g
2h
2i
96
5
86
–55
41
–11
89
84
84
8
21
16
12
40
95
6
30
30
30
24
16
20
9
95
7
G
H
E
E
E
10
11
2j
91
8
Allyl
2k
91
9d
10e
11f
a Reaction conditions: 1 (0.2 mmol), E (10 mol%), KOAc (10 mol%),
Et2O (2.0 mL), 0 °C.
b Isolated yield of 2.
c Determined by HPLC.
a Reaction conditions: 1a (0.2 mmol), catalyst (10 mol%), KOAc (10
mol%), Et2O (2.0 mL), r.t.
graphy on silica gel (EtOAc–hexanes = 1:3) to afford product 2a.
Colorless oil, 41.0 mg, 90% yield, 89% ee [Daicel Chiralcel OJ-H,
n-hexane–2-PrOH (60:40), v = 0.6 mL min–1, λ = 254 nm, tR (major)
b Isolated yield of 2a.
c Determined by HPLC.
d Reaction at 0 °C.
20
= 18.5 min, tR (minor) = 26.2 min]; [α]D = –172.4 (c = 0.40,
e Concentration: 0.05 mol/L of 1a.
f Conditions: KOAc (50 mol%), reaction at 0 °C.
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.85–7.68 (m, 3 H), 7.62–
7.48 (m, 1 H), 6.79 (dd, J = 10.0, 1.2 Hz, 1 H), 6.07 (d, J = 10.0 Hz,
1 H), 3.48 (s, 3 H), 3.39 (d, J = 8.8 Hz, 1 H), 3.32 (d, J = 18.0 Hz, 1
H), 2.85 (dd, J = 18.0, 8.8 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 200.2, 194.7, 153.3, 147.4, 135.6, 134.7, 130.4, 130.1, 124.6,
124.1, 77.8, 52.9, 49.0, 34.4. IR (thin film): νmax = 3056, 2932, 2827,
1718, 1681, 1602, 1462, 1078, 1045, 939, 803, 762, 704 cm–1. MS
(EI): m/z (%) = 228 (96) [M]+, 115 (100). HRMS (EI): m/z calcd for
C14H12O3 [M]+: 228.0786; found: 228.0789.
derived triazolium salt E and 10 mol% of KOAc, various
substituted tricyclic carbocycles bearing a quaternary car-
bon stereogenic center and two contiguous stereocenters
were obtained in excellent yields and enantioselectivities.
General Procedure for Desymmetrization of Cyclohexa-
dienones (Entry 1, Table 4)
Acknowledgment
A flame-dried Schlenk tube was cooled to r.t. and filled with argon.
To this flask were added triazolium salt E (9.7 mg, 0.02 mmol, 10
mol%), Et2O (2.0 mL), and KOAc (2.0 mg, 0.02 mmol, 10 mol%).
The reaction mixture was stirred at r.t. for 30 min. The substrate 1a
(45.6 mg, 0.2 mmol) was then added at 0 °C, and the resulting mix-
ture was stirred at this temperature. After the reaction was complete
(monitored by TLC), the reaction mixture was concentrated under
reduced pressure. The residue was purified by column chromato-
We thank the National Basic Research Program of China (973 Pro-
gram 2009CB825300) and National Natural Science Foundation of
China (20972177, 21025209, 21121062) for generous financial
support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1201–1204

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M.-Q. Jia, S.-L. You
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Synlett 2013, 24, 1201–1204
© Georg Thieme Verlag Stuttgart · New York